Self-injection device

ABSTRACT

A device ( 100 ) for delivering a medicament into a patient&#39;s body by injection into or through the patient&#39;s skin includes a body ( 104, 116 ) having a reservoir ( 160 ) disposed therein for containing the medicament, an injection needle ( 152 ) for penetrating the skin of the patient, the needle ( 152 ) having a lumen and communicating with the reservoir ( 160 ), and a pressurizing system for pressurizing the reservoir ( 160 ). The device also includes indicator means ( 124 ) visible outside the device ( 100 ) for indicating that delivery of the medicament is substantially complete.

FIELD OF THE INVENTION

The present invention relates generally to a substance delivery devicehaving improved patient convenience, ease of use, and efficiency. Thepresent invention also relates generally to a patch-like, self-containedsubstance infusion or self-injection device that can be used to delivera variety of substances or medications to a patient. More specifically,the present invention relates to a patch-like infusion or self-injectiondevice with an end-of-dose indicator.

BACKGROUND OF THE INVENTION

A large number of people, such as those suffering from conditions suchas diabetes, use some form of infusion therapy, such as daily insulininfusions, to maintain close control of their glucose levels. Currently,in the insulin infusion treatment example, there are two principal modesof daily insulin therapy. The first mode includes syringes and insulinpens. These devices are simple to use and are relatively low in cost,but they require a needle stick at each injection typically three tofour times per day. The second mode includes infusion pump therapy,which entails the purchase of an expensive pump that lasts for aboutthree years. The high cost (roughly 8 to 10 times the daily cost ofsyringe therapy) and limited lifetime of the pump are high barriers tothis type of therapy. Insulin pumps also represent relatively oldtechnology and are cumbersome to use. From a lifestyle standpoint,moreover, the tubing (known as the “infusion set”) that links the pumpwith the delivery site on the patient's abdomen is very inconvenient andthe pumps are relatively heavy, making carrying the pump a burden. Froma patient perspective, however, the overwhelming majority of patientswho have used pumps prefer to remain with pumps for the rest of theirlives. This is because infusion pumps, although more complex thansyringes and pens, offer the advantages of continuous infusion ofinsulin, precision dosing and programmable delivery schedules. Thisresults in closer glucose control and an improved feeling of wellness.

Interest in better therapy is on the rise, accounting for the observedgrowth in pump therapy and increased number of daily injections. In thisand similar infusion examples, what is needed to fully meet thisincreased interest is a form of insulin delivery or infusion thatcombines the best features of daily injection therapy (low cost and easeof use) with those of the insulin pump (continuous infusion andprecision dosing) and that also avoids the disadvantages of each.

Several attempts have been made to provide ambulatory or “wearable” druginfusion devices that are low in cost and convenient to use. Some ofthese devices are intended to be partially or entirely disposable. Intheory, devices of this type can provide many of the advantages of aninfusion pump without the attendant cost and inconvenience.Unfortunately, however, many of these devices suffer from disadvantagesincluding patient discomfort (due to the gauge and/or length ofinjection needle used), compatibility and interaction between thesubstance being delivered and the materials used in the construction ofthe infusion device, and possible malfunctioning if not properlyactivated by the patient (for example, “wet” injections resulting frompremature activation of the device). Difficulties in manufacturing andin controlling needle penetration depth have also been encountered,particularly when short and/or fine-gauge injection needles are used.The possibility of needle-stick injuries to those who come into contactwith the used device has also been problematic.

Accordingly, a need exists for an alternative to current infusiondevices, such as infusion pumps for insulin, that further providessimplicity in manufacture and use improvements for insulin andnon-insulin applications.

SUMMARY OF THE INVENTION

An aspect of the present invention is to provide a patch-like infusionor self-injection device that can be conveniently worn against the skinwhile providing infusion of a desired substance, and providing minimaldiscomfort by using one or more microneedles. An additional aspect ofthe present invention is to provide such an infusion or self-injectiondevice having an end-of-dose indicator.

The foregoing and/or other aspects of the present invention are achievedby providing a device for delivering a medicament into a patient's bodyby injection into or through the patient's skin, including a body havinga reservoir disposed therein for containing the medicament, an injectionneedle for penetrating the skin of the patient, the needle having alumen and communicating with the reservoir, and a pressurizing systemfor pressurizing the reservoir. The device also includes indicator meansvisible outside the device for indicating that delivery of themedicament is substantially complete.

The foregoing and/or other aspects of the present invention are alsoachieved by providing a device for delivering a medicament into apatient's body by injection into or through the patient's skin,including a body, a reservoir disposed within the body for containingthe medicament, an injection needle for penetrating the skin of thepatient and administering the medicament from the reservoir, and apressurizing system for pressurizing the reservoir. The device alsoincludes an end-of-dose indicator visible outside the device forindicating that delivery of the medicament is substantially complete.

Additional and/or other aspects and advantages of the present inventionwill be set forth in part in the description that follows and, in part,will be apparent from the description, or may be learned by practice ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and/or other aspects and advantages of embodiments of theinvention will be more readily appreciated from the following detaileddescription, taken in conjunction with the accompanying drawings, ofwhich:

FIG. 1 illustrates a perspective view of an embodiment of a patch-likeinfusion or self-injection device in a pre-activated state prior toactivation;

FIG. 2 illustrates a partially exploded view of the infusion device ofFIG. 1 in the pre-activated state;

FIG. 3 illustrates a partially exploded view of the infusion device ofFIG. 1 in the pre-activated state with an activator button rotated awayto reveal more detail;

FIG. 4 illustrates a more fully exploded view of the infusion device ofFIG. 1 in the pre-activated state;

FIG. 5 illustrates a cross-sectional view of the infusion device of FIG.1 in the pre-activated state;

FIG. 6 illustrates a cross-sectional view of the infusion device of FIG.1 in the pre-activated state with the activator button rotated away;

FIG. 7 illustrates a partially exploded view of the infusion device ofFIG. 1 during installation of a safety mechanism;

FIG. 8 illustrates a partially exploded view of the infusion device ofFIG. 1 subsequent to activation;

FIG. 9 illustrates a more fully exploded view of the infusion device ofFIG. 1 subsequent to activation;

FIG. 10 illustrates a cross-sectional view of the infusion device ofFIG. 1 subsequent to activation;

FIG. 11 illustrates a partially exploded view of the infusion device ofFIG. 1 subsequent to deployment of the safety mechanism;

FIG. 12 illustrates a cross-sectional view of the infusion device ofFIG. 1 subsequent to deployment of the safety mechanism;

FIG. 13 illustrates a bottom surface of the safety mechanism;

FIG. 14 further illustrates the structure of the safety mechanism;

FIGS. 15A-15D illustrate an end-of-dose indicator and the operationthereof in the infusion device of FIG. 1;

FIGS. 16A and 16B illustrate another end-of-dose indicator and theoperation thereof in the infusion device of FIG. 1;

FIGS. 17A and 17B illustrate yet another end-of-dose indicator;

FIG. 18 illustrates the end-of-dose indicator of FIG. 17A disposed inthe infusion device of FIG. 1;

FIGS. 19A and 19B illustrate still another end-of-dose indicator and theoperation thereof;

FIGS. 20A and 20B indicate the operation of the end-of-dose indicator ofFIG. 19A in the infusion device of FIG. 1;

FIGS. 21A and 21B illustrate still another end-of-dose indicator and theoperation thereof;

FIGS. 22A and 22B indicate the operation of the end-of-dose indicator ofFIG. 21A in the infusion device of FIG. 1;

FIGS. 23A-23C illustrate embodiments of markers for indicating progressof delivery of a medicament;

FIGS. 24A and 24B illustrate a further end-of-dose indicator and theoperation thereof;

FIGS. 25A and 25B indicate the operation of the end-of-dose indicator ofFIG. 24A in the infusion device of FIG. 1;

FIGS. 26A and 26B illustrate another end-of-dose indicator and theoperation thereof;

FIGS. 27A and 27B indicate the operation of the end-of-dose indicator ofFIG. 26A in the infusion device of FIG. 1; and

FIG. 28 illustrates an embodiment of an infusion device with aninjection port.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to embodiments of the presentinvention, examples of which are illustrated in the accompanyingdrawings, wherein like reference numerals refer to the like elementsthroughout. The embodiments described exemplify the present invention byreferring to the drawings.

The embodiments of the present invention described below can be used asa convenient, patch-like infusion or self-injection device 100 todeliver a pre-measured dose of a substance, such as a liquid drug ormedication, to a patient over a period of time or all at once. Thedevice is preferably provided to the end user in a pre-filled condition,that is, with the drug or medication already in the device reservoir.Though the patch-like infusion or self-injection device 100 (shown, forexample, in FIG. 1) described herein can be employed by a patient and/ora caregiver, for convenience, a user of the device is hereinafterreferred to as a “patient.” Additionally, for convenience, terms such as“vertical” and “horizontal” and “top” and “bottom” are employed torepresent relative directions with respect to an infusion device 100disposed on a horizontal surface. It will be understood, however, thatthe infusion device 100 is not limited to such an orientation, and thatthe infusion device 100 may be employed in any orientation. Further, thealternative use of the terms “infusion device” and “self-injectiondevice” to describe devices embodying the present invention is notintended in a limiting sense. Infusion devices that do not have aself-injection capability are within the scope of the present invention,as are self-injection devices that do not carry out continuous infusion.For convenience, but not by way of limitation, the term “infusiondevice” is used in the description that follows.

The patch-like infusion device 100 of FIG. 1 is self-contained and isattached to the skin surface of the patient by adhesive disposed on abottom surface of the infusion device 100 (as will be described ingreater detail below). Once properly positioned and activated by thepatient, the pressure of a released spring on a flexible reservoirwithin the device can be used to empty the contents of the reservoirthrough one or more patient needles (for example, microneedles) via aneedle manifold. The substance within the reservoir is then deliveredthrough the skin of the patient by the microneedles, which are driveninto the skin. It will be understood that other embodiments are possiblein which the spring is replaced with a different type of stored energydevice, which may be mechanical, electrical and/or chemical in nature.

As will be appreciated by one skilled in the art, there are numerousways of constructing and using the patch-like infusion device 100disclosed herein. Although reference will be made to the embodimentsdepicted in the drawings and the following descriptions, the embodimentsdisclosed herein are not meant to be exhaustive of the variousalternative designs and embodiments that are encompassed by thedisclosed invention. In each disclosed embodiment, the device isreferred to as an infusion device, but the device may also injectsubstances at a much faster (bolus) rate than is commonly accomplishedby typical infusion devices. For example, the contents can be deliveredin a period as short as several seconds or as long as several days.

In an embodiment of the device shown in FIGS. 1 through 12, apush-button design of the patch-like infusion device 100 is shownwherein the activation and energizing of the device is accomplished in asingle multi-function/step process. FIG. 1 illustrates an assembledembodiment of the infusion device 100 in a pre-activated state. FIGS.2-6 illustrate partially exploded and cross-sectional views of theinfusion device 100 in the pre-activated state, FIG. 7 illustrates apartially exploded view of the infusion device 100 during installationof a safety mechanism, FIGS. 8-10 illustrate exploded andcross-sectional views of the infusion device 100 subsequent toactivation, and FIGS. 11 and 12 illustrate exploded and cross-sectionalviews of the infusion device 100 subsequent to deployment of the safetymechanism. The infusion device 100 is configured to operate between thepre-activated state (shown, for example, in FIGS. 1, 2, and 5), anactivated or fired state (shown, for example, in FIGS. 8-10), and aretracted or safe state (shown, for example, in FIGS. 11 and 12).

As shown in FIG. 1, an embodiment of the patch-like infusion device 100includes a bottom enclosure 104, a safety mechanism 108, a flexibleneedle cover 112, a top enclosure 116, a reservoir subassembly 120, anend-of-dose indicator (EDI) 124, and an activator button 128, whichincludes a patient interface surface 132. Additionally, as shown inFIGS. 2-6, the infusion device 100 also includes a rotor or activationring 136, a pressurization spring 140, a dome-like metal plunger 144,and a drive spring 148.

The flexible needle cover 112 provides patient and device safety byprotecting at least one needle 152 (described in greater detail below)and providing a sterile barrier. The needle cover 112, protects theneedle 152 during device manufacture, protects the patient prior to use,and provides a sterility barrier at any point prior to removal.According to one embodiment, the needle cover 112 is attached via apress fit with a needle manifold in which the at least one needle 152 isdisposed. Additionally, according to one embodiment, a needle opening156 (described in greater detail below) of the safety mechanism 108 isshaped to closely correspond to a perimeter of the needle cover 112.

As shown, for example, in FIGS. 2, 3, 5, 6, 8, 10, and 12, the reservoirsubassembly 120 includes a reservoir 160, a reservoir dome seal 164, avalve 168, at least one needle 152, and at least one channel 172 (see,for example, FIG. 8) disposed between the valve 168 and the needle 152and creating a flow path therebetween. The reservoir 160 includes a dome176. Additionally, the reservoir subassembly 120 includes the removableneedle cover 112 to selectively cover the at least one needle 152.According to one embodiment, the reservoir subassembly 120 also includesa reservoir arm seal 180, covering the channel 172. Preferably, theneedle 152 includes a needle manifold and a plurality of microneedles152.

The reservoir dome seal (flexible film) 164 of the reservoir subassembly120, as shown, for example, in FIG. 5, is disposed between the plunger144 and the dome 176. Reservoir contents (for example, medicinalmaterial) for the infusion device 100 are disposed in the space betweenthe reservoir dome seal 164 and the dome 176. The combination of thereservoir dome seal 164, the dome 176, and the space therebetweendefines a reservoir 160. The dome 176 is preferably transparent topermit viewing of the reservoir contents. The reservoir dome seal 164can be made of non-distensible materials or laminates, such asmetal-coated films or other similar substances. For example, onepossible flexible laminate film that can be used in the reservoir domeseal 164 includes a first polyethylene layer, a second chemical layer asknown to those skilled in the art to provide an attachment mechanism fora third metal layer which is chosen based upon barrier characteristics,and a fourth layer that includes polyester and/or nylon. By utilizing ametal-coated or metallized film in conjunction with a rigid portion (forexample, dome 176), the barrier properties of the reservoir 160 areimproved, thereby increasing or improving the shelf life of the contentscontained within. For example, where a reservoir content includesinsulin, the primary materials of contact in the reservoir 160 includelinear, low-density polyethylene (LLDPE), low-density polyethylene(LDPE), cyclic olefin copolymer (COC) and Teflon. As described ingreater detail below, the primary materials of contact in the remainingflow path of the reservoir contents may also include COC and LLDPE, aswell as thermoplastic elastomer (TPE), medical grade acrylic, stainlesssteel, and a needle adhesive (e.g. a UV cured adhesive). Such materialsthat remain in extended contact with the contents of the reservoir 160preferably pass ISO 10-993 and other applicable biocompatibilitytesting.

The reservoir subassembly 120 is further preferably able to be storedfor the prescribed shelf life of the reservoir contents in applicablecontrolled environments without adverse effect to the contents, and iscapable of applications in a variety of environmental conditions.Additionally, the barrier provided by the components of the reservoirsubassembly 120 do not permit the transport of gas, liquid, and/or solidmaterials into or out of the contents at a rate greater than thatallowable to meet the desired shelf life. In the embodiments shownabove, the reservoir materials are capable of being stored and operatedin a temperature range of approximately 34 to 120 degrees Fahrenheit andcan have a shelf life of two or more years.

In addition to satisfying stability requirements, the reservoirsubassembly 120 can further ensure operation by successfully passing anynumber of leak tests, such as holding a 30 psi sample for 20 minuteswithout leaking. Additional filling, storage and delivery benefitsresulting from the configuration of the reservoir include minimizedheadspace and adaptability as described in greater detail below.

In one embodiment, the reservoir 160 is evacuated prior to filling. Byevacuating the reservoir 160 prior to filling and having only a slightdepression in the dome 176, headspace and excess waste within thereservoir 160 can be minimized. In addition, the shape of the reservoircan be configured to adapt to the type of energizing mechanism (forexample, pressurization spring 140 and plunger 144) used. Additionally,using an evacuated flexible reservoir 160 during filling minimizes anyair or bubbles within the filled reservoir 160. The use of a flexiblereservoir 160 is also very beneficial when the infusion device 100 issubjected to external pressure or temperature variations, which can leadto increased internal reservoir pressures. In such case, the flexiblereservoir 160 expands and contracts with the reservoir contents, therebypreventing possible leaks due to expansion and contraction forces.

Yet another feature of the reservoir 160 includes the ability to permitautomated particulate inspection at the time of filling, or by a patientat the time of use. One or more reservoir barriers, such as the dome176, can be molded of a transparent, clear plastic material, whichallows inspection of the substance contained within the reservoir. Thetransparent, clear plastic material is preferably a cyclic olefincopolymer that is characterized by high transparency and clarity, lowextractables, and biocompatibility with the substance contained in thereservoir 160. A suitable material is available from Zeon Chemicals,L.P., of Louisville, Ky. under the designation “BD CCP Resin,” and islisted by the U.S. Food and Drug Administration and DMF No. 16368. Insuch applications, the reservoir 160 includes minimal features thatcould possibly obstruct inspection (i.e. rotation during inspection ispermitted).

Channel arm 172 is provided in the form of at least one flexible arcuatearm extending from the valve 168 to the needle manifold or microneedles152. The arcuate arm has a groove 174 (see, for example, FIG. 2) formedtherein. To provide a fluid path between valve 168 and the needlemanifold or microneedles 152, the reservoir arm seal 180 covers thegroove 174. The fluid path (disposed in channel arm 172—shown, forexample, in FIG. 8) between the reservoir 160 and the microneedles 152is constructed of materials similar or identical to those describedabove for the reservoir 160. For example, channel arm 172 may beconstructed of the same material as the dome 160 and the reservoir armseal 180 may constructed of the same material as the reservoir dome seal164. According to one embodiment, both channel arms 172 are employed asfluid paths between the valve 168 and the needle manifold ormicroneedles 152. According to another embodiment, only one of thechannel arms 172 is employed as a fluid path, and the remaining channelarm 172 provides structural support. In such an embodiment, the groove174 extends fully from the valve 168 to the needle manifold ormicroneedles 152 only in the channel arm 174 that will be employed asthe fluid path.

The channel arm 172 must be sufficiently flexible to withstand the forceof activation. Contrasting the position of the channel arm 172 in FIGS.2 and 8, the channel arm 172 (covered by reservoir arm seal 180 in FIG.2, which is removed in FIG. 8 for clarity) elastically deforms when themicroneedles 152 are driven into the patient's skin (described ingreater detail below). During such deformation, the channel arm 172 mustmaintain the integrity of the fluid path between the valve 168 and theneedle manifold or microneedles 152. Additionally, the materials for thechannel arm 172 satisfy numerous biocompatibility and storage tests. Forexample, as shown in Table 1 below, where an infusion device contentincludes insulin, the primary materials of contact in the reservoir 160include linear, low-density polyethylene, cyclic olefin copolymer, andTeflon, and can also include a transparent, clear plastic. The primarymaterials of contact in the remaining flow path (channel 62) between thereservoir 160 and the microneedles 152 of the needle manifold includeCOC and/or medical grade acrylic, LLDPE, TPE, and stainless steel, aswell as the needle adhesive.

TABLE 1 Path Component Material Reservoir Polyethylene, cyclic olefincopolymer, and/or Teflon Reservoir Dome Seal Metal-coated film, such aspolyethylene, aluminum, polyester, and/or nylon with a chemical tielayer Valve TPE Needle Manifold COC and/or medical grade acrylic Needleadhesive UV-cured adhesive Microneedle Stainless steel

More specifically, the microneedles 152 can be constructed of stainlesssteel, and the needle manifold can be constructed of polyethylene and/ormedical grade acrylic. Such materials, when in extended contact with thecontents of the reservoir, preferably pass ISO 10-993 biocompatibilitytesting.

The valve 168, disposed between the reservoir 160 and the channel 172,selectively permits and restricts fluid flow between the reservoir 160and the channel 172. The valve 168 moves between a pre-activatedposition (shown, for example, in FIGS. 2, 3, and 6) and an activatedposition (shown, for example, in FIGS. 8-10). When in the activatedposition, the valve permits fluid flow between the reservoir 160 and thechannel 172, and therefore to the needle manifold and microneedles 152.

In use, the valve 168 will eventually be pushed into the activatedposition by the movement of the activator button 128, best illustratedby the movement of the valve 168 between FIGS. 5 and 10. As shown inFIG. 10, the movement of the valve 168 advances the enlarged distal endof the valve 168, thereby permitting the drug to flow from the reservoir160 into the channel 172 and down the fluid path to the needle manifold.

The embodiment described above includes at least one needle 152, ormicroneedle 152, but may contain several, such as the two illustratedmicroneedles 152. Each microneedle 152 is preferably at least 31 gaugeor smaller, such as 34 gauge, and is anchored within a patient needlemanifold that can be placed in fluid communication with the reservoir160. The microneedles 152, when more than one is included in theinfusion device 100, can also be of differing lengths, or gauges, or acombination of both differing lengths and gauges, and can contain one ormore ports along a body length, preferably located near the tip of themicroneedle 152 or near the tip bevel if any of the microneedles 152 hasone.

According to one embodiment, the gauge of the microneedles 152 governsthe delivery rate of reservoir contents of the infusion device 100. Theuse of multiple 34 gauge microneedles 152 to deliver the reservoircontents is practical when the infusion occurs over a longer period thantypically associated with an immediate syringe injection requiring amuch larger cannula, or needle. In the disclosed embodiments, anymicroneedles 152 that target either an intradermal or subcutaneous spacecan be used, but the illustrated embodiments include intradermalmicroneedles 152 of between 1 and 7 mm in length (i.e., 4 mm). Thearrangement of the microneedles 152 can be in a linear or nonlineararray, and can include any number of microneedles 152 as required by thespecific application.

As noted above, the microneedles 152 are positioned in a needlemanifold. In the needle manifold, at least one fluid communication path,or channel 172, is provided to each microneedle 152. The manifold maysimply have a single path to one or more microneedles 152, or mayprovide multiple fluid paths or channels routing the reservoir contentsto each microneedle 152 separately. These paths or channels may furthercomprise a tortuous path for the contents to travel, thereby affectingfluid pressures and rates of delivery, and acting as a flow restrictor.The channels or paths within the needle manifold can range in width,depth and configuration depending upon application, where channel widthsare typically between about 0.015 and 0.04 inch, preferably 0.02 inch,and are constructed to minimize dead space within the manifold.

According to one embodiment, the reservoir subassembly 120 has a pair ofholes 184 and 188 to aid registration of the reservoir subassembly 120with respect to the bottom enclosure 104. First and second posts 192 and196 (described in greater detail below) of the bottom enclosure 104 areinserted through the respective holes 184 and 188.

In exploded views with the reservoir subassembly 120 removed, FIGS. 4,7, and 9 illustrate that bottom enclosure 104 includes a substantiallycylindrical housing 200 in which pressurization spring 140 and plunger144 are disposed. According to one embodiment, cylindrical housing 200includes a plurality of recessed channels 204 to guide a respectiveplurality of legs 208 and feet 212 of the plunger 144 as the plungertranslates within the housing 200. Collectively, a leg 208 and a foot212 constitute a plunger tab 214. As shown in FIGS. 4, 7, and 9, forexample, the recessed channels 204 extend only part of the way down thecylindrical housing 200 from a top thereof. Below the recessed channels204, there are openings 216 through which the feet 212 of plunger 144can extend outside of the cylindrical housing 200. The openings 216 aresubstantially L-shaped with horizontal portions at the base of thecylindrical housing 200, and a vertical portion substantially alignedwith the recessed channels 204.

When the infusion device 100 is in the pre-activated state, thepressurization spring 140 is compressed by the plunger 144 (as shown,for example, in FIGS. 4-6), and the feet 212 of the plunger 144 aresubstantially disposed in the horizontal portions of the openings 216.The force of the pressurization spring 140 biases the feet 212 of theplunger 144 against a top of the horizontal portions of the openings 216(i.e., a ledge of the cylindrical housing 200). Together, as describedin greater detail below, the pressurization spring 140 and the plunger144 form a pressurization system to pressurize the reservoir 160 whenthe infusion device 100 is activated.

As described in greater detail below, the rotor 136 rotates around thebase of the cylindrical housing 200 between a pre-activated position(illustrated, for example, in FIGS. 2-4) and an activated position(illustrated, for example, in FIGS. 8-10). When the rotor 136 rotatesfrom the pre-activated position to the activated position, at least onefoot engaging surface 220 (shown, for example, in FIG. 4) of the rotor136 engages at least one of the feet 212 of the plunger 144 and rotatesthe plunger 144 so that the feet 212 align with the vertical portions ofthe openings 216 and the recessed channels 204. At this point, thepressurization spring 140 moves the plunger 144 upward with the feet 212being guided by the raised channels 204.

The pressurization spring 140 is included in the infusion device 100 toapply an essentially even force to the reservoir 160, to force thecontents from the reservoir 160. The pressurization spring 140 is usedto store energy that, when released, pressurizes the reservoir 160 atthe time of use. The pressurization spring 140 is held in a compressedstate by engagement between feet 212 of the plunger 144 and thecylindrical housing 200. This engagement prevents the pressurizationspring 140 from putting stress on a film (to be described later) of thereservoir 160 or any remaining device components (other than the bottomenclosure 104 and the plunger 144) during storage. The plunger 144 issufficiently rigid to resist spring tension and deformation, and shouldnot fail under normal load.

As noted above, when the rotor 136 rotates from the pre-activatedposition to the activated position, the rotor 136 engages at least oneof the feet 212 of the plunger 144 and rotates the plunger 144 to alignthe feet 212 with the vertical portions of the openings 216 and therecessed channels 204. The compressed pressurization spring 140, thenmoves the plunger 144 upward, and in doing so, exerts a force on thefilm of the reservoir 160. The pressurization spring 140 can beconfigured to preferably create a pressure within the reservoir 116 offrom about 1 to 50 psi, and more preferably from about 2 to about 25 psifor intradermal delivery of the reservoir contents. For sub-cutaneousinjection or infusion, a range of about 2 to 5 psi may be sufficient.

According to one embodiment, the activator button 128 includes thepatient interface surface 132 that the patient presses to activate theinfusion device 100. The activator button 128 also includes a hinge arm224 and an activation arm 228 (both shown, for example, in FIG. 3). Thehinge arm 224 of the activator button 128 includes a cylindrical portionwith an opening. The activation arm 228 includes a tab 230 (see, forexample, FIG. 3). According to one embodiment, the tab 230 includes abearing surface 232 and a locking surface 234 disposed adjacent to thecantilevered end of the bearing surface 232. According to oneembodiment, the tab 230 forms an acute angle with a main portion of theactivation arm 228.

The first post 192, disposed on the bottom enclosure 104, extendsupwardly therefrom. According to one embodiment (as shown, for example,in FIGS. 4 and 7), a base of the first post 192 includes a pair of flatsides 236 and a pair of rounded sides 240. Additionally, as shown, forexample, in FIGS. 4 and 7, the second post 196 and first and seconddrive spring bases 244 and 248 extend upwardly from the bottom enclosure104. As will be described in greater detail below, the first and seconddrive spring bases 244 and 248 anchor respective ends of drive spring148. The first drive spring base 244 is disposed adjacent to the secondpost 196 with a space therebetween.

According to one embodiment, FIGS. 3 and 6 illustrate the positioning ofthe activator button 128 with respect to the bottom enclosure 104, forassembly of the activator button 128. In this position, the opening ofthe cylindrical portion of the hinge arm 224 allows the activator button128 to slide horizontally (passing the flat sides 236) and engage thefirst post 192. The hinge arm 224 (and therefore the activator button128) can then rotate about the first post 192. As the activation arm 228passes into the space between the second post 196 and the first drivespring base 244, at least one of the tab 230 and the activation arm 228elastically deforms until a cantilevered end of the bearing surface 232of tab 230 passes a retaining face 252 of the second post 196. Thepassage of the cantilevered end of the bearing surface 232 of tab 230past the retaining face 252 (see, for example, FIG. 4) of the secondpost 196 and the engagement of the locking surface 234 of tab 230 withthe retaining face 252 provides an audible click and tactile feedbackconveying that the activator button 128 is in the pre-activatedposition.

Referring back to FIGS. 2-4, and 7-9, rotor 136 additionally includes anactivation projection 256 and a drive spring holder 260. The activationarm 228 of the activator button 128 engages the activation projection256 when a patient depresses the activator button 128, thereby rotatingthe rotor 136 from the pre-activated position to the activated position.

The drive spring holder 260 maintains the drive spring 148 in apre-activated position when the rotor 136 is in the pre-activatedposition. As noted previously, the first and second drive spring bases244 and 248 anchor opposing ends of the drive spring 148. Atapproximately a midpoint of the drive spring 148, there is asubstantially U-shaped projection as shown, for example, in FIGS. 2 and3, for engagement with the drive spring holder 260 of the rotor 136.Accordingly, when the rotor 136 is in the pre-activated position and thedrive spring 148 engages the drive spring holder 260, the drive spring148 is maintained in a tensile state. And when the drive spring holder260 releases the drive spring 148 (i.e., when the rotor rotates from thepre-activated position to the activated position as illustrated, forexample, in FIGS. 8-10), the drive spring 148 drives the microneedles152 to extend outside of the infusion device 100 through an opening 300in the bottom enclosure 104 (and through an opening in the safetymechanism 108 described in greater detail below).

Thus, as will be described in greater detail below, the activation andenergizing of the infusion device 100 that is accomplished in a singlemulti-function/step process includes depression of the activator button128 by a patient, and rotation of the rotor 136 due to engagementbetween the activation arm 228 of the activator button 128 and theactivation projection 256 of the rotor 136. As described above, therotation of the rotor 136 rotates and releases the plunger 144 topressurize the fluid within the reservoir 160. Additionally, therotation of the rotor 136 releases the drive spring 148 from the drivespring holder 260, thereby driving the microneedles 152 to extendoutside of the infusion device 100. The single multi-function/stepprocess also includes movement of the valve 168 from the pre-activatedposition to the activated position due to the activator button 128engaging and moving the valve 168 when the activator button 128 isdepressed, thereby commencing fluid flow between the reservoir and themicroneedles 152 via the channel 172.

As noted above, the patch-like infusion device 100 also includes asafety mechanism 108. To prevent inadvertent or accidental needle stickinjuries, prevent intentional re-use of the device, and to shieldexposed needles, the locking needle safety mechanism 108 is provided.The safety mechanism 108 automatically activates immediately uponremoval of the infusion device 100 from the skin surface of the patient.According to one embodiment described in greater detail below, aflexible adhesive pad 264 adheres to a bottom portion of the bottomenclosure 104 and a bottom portion of the safety mechanism 108. Theadhesive pad 264 contacts with the patient's skin and holds the infusiondevice 100 in position on the skin surface during use. As shown, forexample, in FIGS. 11 and 12, upon removal of the infusion device 100from the skin surface, the safety mechanism 108 extends to a positionshielding the microneedles 152. When fully extended, safety mechanism108 locks into place and prevents accidental injury or exposure to thepatient needles 152.

In general, a passive safety system is most desirable. This allows thedevice to be self-protecting in case of accidental removal or if thepatient forgets that there is a safety step. Because one typical use forthis infusion device 100 is to provide human growth hormone, which isusually given in the evening, it can be expected that patients that wearthe device (such as children) may actually wear them overnight, eventhough the delivery may be expected to take less than 10 minutes.Without a passive system, if the infusion device 100 falls off, themicroneedles 152 could re-stick the patient or a caregiver. The solutionis to either limit the activities during use, or include a passivesafety system.

With respect to safety systems, there are typically three options. Afirst option is to retract the needles 152 into the device. A secondoption is to shield the needles 152 to remove access, and a third optionis to destroy the needles 152 in a way that prevents needle stickinjuries. Other systems, such as active systems, utilize manualshielding and/or destruction, or manual release of safety features withan additional button push or similar action. A detailed description ofpassive safety embodiments of the present invention is described below.

One safety embodiment of the present invention is a passive, fullyenclosed pull-out design embodiment, such as safety mechanism 108. FIGS.5, 10, and 12 are perspective cutaway views of the infusion device 100that illustrate the safety mechanism 108 prior to activation, subsequentto activation, and subsequent to deployment of the safety mechanism 108,respectively.

When the infusion device 100 is removed from the skin, the flexibleadhesive pad 264 (attached to both the bottom surface of the bottomenclosure 104 and the bottom surface of the safety mechanism 108) willpull the safety mechanism 108 out and lock it into place before theadhesive pad 264 releases the skin surface. In other words, the forcerequired to remove the adhesive pad from the skin surface is greaterthan that required to deploy the safety mechanism 108. According to oneembodiment, the safety mechanism 108, as shown, for example, in FIG. 13,includes a flat surface portion 268 that is in contact with thepatient's skin. The flat surface 268 is where a portion of adhesive pad264 (shown as a dotted line in FIG. 13) is affixed to safety mechanism108 such that when the infusion device 100 is removed by the patientfrom the skin, the adhesive pad 264 will act to deploy the safetymechanism 108 from the infusion device 100, thereby shielding themicroneedles 152, which otherwise would be exposed upon removal of theinfusion device 100 from the patient. When the safety mechanism 108 isfully extended, the safety mechanism 108 locks into place and preventsaccidental injury or exposure to the microneedles 152.

According to one embodiment, the adhesive pad 264 is provided insubstantially two parts, one on the bulk of the bottom surface of thebottom enclosure 104, and one on the bottom surface of the safetymechanism 108. When the infusion device 100 is removed, the two patchesmove independently and the safety mechanism 108 is rotatable withrespect to the bottom enclosure 104. According to another embodiment,the two parts are formed as a unitary, flexible adhesive pad 264 withone part being disposed on the on the bulk of the bottom surface of thebottom enclosure 104, and one part disposed on the bottom surface of thesafety mechanism 108.

According to one embodiment, the safety mechanism 108 is a stamped metalpart. According to another embodiment, the safety mechanism 108 is madeof substantially the same material as the bottom enclosure 104. As shownin FIG. 14, the safety mechanism 108 includes a front shield 272, a pairof insertion tabs 276 disposed at a rear portion of the safety mechanism108, a pair of pivot tabs 280 disposed, respectively, at upper rear endsof a rim portion 284 of the safety mechanism 108, a guide post 288extending upwardly from a substantially flat bottom inner surface of thesafety mechanism 108, and locking posts 292 also extending upwardly fromthe bottom inner surface of the safety mechanism 108. Front shield 272extends above the rim portion 284 to shield the patient from themicroneedles 152 when the safety mechanism 108 is deployed. The guidepost 288 includes a cutout therein to engage a safety retainingprojection 296 of the rotor 136 (shown, for example, in FIGS. 7 and 9)when the rotor 136 is in the pre-activated position, to prevent thesafety mechanism 108 from deploying prior to activation of the infusiondevice 100.

Additionally, as noted above, the safety mechanism 108 includes theneedle opening 156. Prior to deployment of the safety mechanism 108, theneedle opening 156 at least partially overlaps the opening 300 in bottomenclosure 104 to provide space for movement of the microneedles 152. Thelocking posts 292 are respectively disposed adjacent to front side edgesof the needle opening 156. The bottom enclosure 104 includes a guidepostopening 304 (shown, for example, in FIGS. 7 and 9), a pair of insertiontab openings 308 (one of which is shown, for example, in FIG. 4)disposed adjacent to opposing side edges of the bottom enclosure 104,and a pair of pivot rests 312 disposed on opposing sides of the bottomenclosure 104 (shown, for example, in FIGS. 7 and 9).

Referring again to FIG. 14, insertion tabs 276 each include a connectingportion 316 and an extending portion 320. According to one embodiment,the connecting portions 316 extend from the bottom inner surface of thesafety mechanism 108 toward a rear of the infusion device 100 at anon-perpendicular angle with respect to the bottom inner surface of thesafety mechanism 108. Extending portions 320 each extend substantiallyperpendicularly from the extending portions 320 toward respective outersides of the safety mechanism 108. To assemble the safety mechanism 108to the bottom enclosure 104, safety mechanism 108 is held at anapproximately 45° angle with respect to the bottom enclosure 104 and theinsertion tabs 276 are inserted through the insertion tab openings 308.The safety mechanism 108 is then rotated to a position such that theguidepost 288 is inserted through the guidepost opening 304 and thebottom inner surface of the safety mechanism 108 is substantiallyparallel and in contact with the bottom surface of the bottom enclosure104.

Referring again to FIGS. 7 and 9, although these views illustrate therotor 136 in the activated position, the exploded nature of FIGS. 7 and9 is convenient to illustrate this stage of the assembly of the safetymechanism 108 to the bottom enclosure 104. It will be understood,however, that the safety mechanism 108 should be assembled to the bottomenclosure prior to activation. Subsequent to the upward rotation of thesafety mechanism 108, as shown in FIG. 4, safety mechanism 108translates rearward with respect to the bottom enclosure 104 such thatpivot tabs 280 clear respective front edges of the pivot rests 312 andare disposed above the pivot rests 312, the locking posts 292 aredisposed adjacent to side edges of the opening 300 of the bottomenclosure 104, and the safety retaining projection 296 of the rotor 136engages the guide post 288.

Returning to FIG. 14, each of the locking posts 292 includes a postextending portion 324 extending substantially perpendicular from theflat bottom inner surface of the safety mechanism 108, and a wedgeportion 328 disposed at an end of the post extending portion 324. As aheight of the wedge portion 328 increases with respect to the bottominner surface of the safety mechanism 108, a width of the wedge portion328 increases.

As the safety mechanism 108 deploys and rotates downward with respect tothe bottom enclosure 104, the wedge portions 328 act against respectiveside edges of the openings 180 of the bottom enclosure 104, causing thelocking posts 192 to deform elastically toward one another. As thesafety mechanism 108 is fully deployed, the tabs 280 become seated inpivot rests 312. Additionally, top edges of the wedge portions 328 passbottom edges of the opening 300 and the locking posts 292 snap back totheir substantially un-deformed states, providing an audible click andtactile feedback communicating that the safety mechanism 108 is fullydeployed, and therefore, that the microneedles 152 are covered.Returning to FIGS. 11 and 12, once the safety mechanism 108 is fullydeployed and the locking posts 292 have snapped back to theirsubstantially un-deformed states, the top edges of the wedge portions328 engage the bottom surface of the bottom enclosure 104 adjacent tothe opening 300, thereby preventing the safety mechanism 108 fromrotating upward with respect to the bottom enclosure 104 and exposingthe microneedles 152. Additionally, as noted above, front shield 272shields the patient from the microneedles 152.

Accordingly, the safety mechanism 108 is a passive safety embodimentprovided as a single part and provides a good lock that will not crushunder human loads. With this passive safety mechanism, no additionalforces are applied to the skin during injection, and the microneedles152 are safely held within the infusion device 100 after use.

After use of the infusion device 100, the patient can once again inspectthe device to ensure the entire dose was delivered. In this regard,according to one embodiment as shown in FIGS. 15A-D, the infusion device100 includes the end-of-dose indicator (EDI) 124. The EDI 124 includes amain body or post 332 and first and second arms 336 and 340 extendingsubstantially horizontally with respect to a top of the main body 332.

The EDI 124 also includes a spring arm 344 that curves upwardly from thetop of the main body 332. According to one embodiment, the spring arm344 pushes against a bottom side of the reservoir subassembly 120,elastically biasing the EDI 124 toward the bottom enclosure 104, toensure that the EDI 124 does not move freely out of the infusion device100, for example, during shipping and handling of the infusion device100. According to one embodiment, the spring arm 344 pushes against abottom side of the dome 176.

Returning to FIG. 4, the main body 332 is disposed in an EDI channel 348and translates substantially vertically therein. According to oneembodiment, the EDI channel is disposed adjacent to one of the recessedchannels 204 that guides legs 208 and feet 212 of plunger 144. The firstarm 336 extends across a top of this recessed channel 204.

Returning to FIG. 15A, a vertical extrusion or signaling post 352extends upwardly from an end of the second arm 340. When the reservoircontents have been delivered, the signaling post 352 extends through anEDI opening 356 (see, for example, FIG. 15C) in the top enclosure 116 tocommunicate that the end of the dose has been reached. According to oneembodiment, the EDI 124 is formed as a one-piece construction.

As shown in FIG. 15B, as the plunger 144 travels upwardly in thecylindrical housing 200 due to the pressurization spring 140 subsequentto activation, one of the feet 212 of the plunger 144 contacts the firstarm 336 of the EDI 124. The foot 212 lifts the EDI 124 upward,overcoming the bias of the spring arm 344, and causing the signalingpost 352 to increasingly extend through the EDI opening 356 duringdelivery of the reservoir contents. Referring back to FIG. 10, as themedicament is being expelled from the reservoir 160 subsequent toactivation, the signaling post 352 partially extends from the infusiondevice 100. Once the delivery of the reservoir contents is complete andthe plunger has achieved its full stroke, the vertical extrusion 352 isfully extended, as shown in FIG. 15D. Thus, the EDI 124 employs thelinear movement of the plunger 144 to generate linear movement of theEDI 124 that is visible outside the infusion device 100, therebycommunicating the delivery of the reservoir contents.

FIGS. 16A and 16B illustrate another end-of-dose indicator (EDI) 360 andthe operation thereof in the infusion device 100. As shown in FIG. 16A,a base 364 of a signaling post 368 of the EDI 360 is a different colorthan the remainder of the signaling post 368. As shown in FIG. 16B,visibility of the base 364 outside the infusion device 100 signals thatdelivery of the medicament is substantially complete. In other respects,the EDI 360 is substantially similar to the EDI 124.

FIGS. 17A and 17B illustrate yet another end-of-dose indicator (EDI)372. As shown in FIGS. 17A and 17B, the EDI 372 includes a main body376, a first arm 380 extending from the main body 376, and first andsecond spring arms 384 and 388 also extending from the main body 376.Additionally, a signaling post 392 extends from an end of the first arm380. According to one embodiment, the signaling post 392 includes a base396 and a top 400. According to one embodiment, at least a portion ofthe base 396 is a different color than the remainder of the signalingpost 392. In such an embodiment, visibility of the different-coloredportion of the base 396 outside the infusion device 100 signals thatdelivery of the medicament is substantially complete.

As shown in FIG. 17A, the EDI 372 also includes a pair of stabilizingarms 412 and 416 extending from the main body 376. The stabilizing arms412 and 416 stabilize the EDI 372 during the movement thereof. FIG. 18illustrates the EDI 372 disposed in the infusion device. As shown inFIG. 18, the cylindrical housing 200 includes a channel 420 movablyhousing the main body 376 of the EDI 372. The stabilizing arms 412 and416 contact an outside of the cylindrical housing 200 to stabilize theEDI 372 during the movement thereof.

Subsequent to activation, as the plunger 144 travels within thecylindrical housing 200, a foot 212 of the plunger 144 contacts andlifts the main body 376 of the EDI 372, thereby converting a motion ofthe plunger 144 into motion of the main body 376, and thus motion of thesignaling post 392.

The first and second spring arms 384 and 388 each have a spring arm post404, 408 disposed at respective ends thereof. According to oneembodiment, the spring arm posts 404 and 408 contact a bottom side ofthe reservoir subassembly 120, elastically biasing the EDI 372 inwardlywith respect to the top enclosure 116 in combination with the springarms 384 and 388, to ensure that the EDI 372 does not extend out of theinfusion device 100 prior to the end of the dosage, for example, duringshipping and handling of the infusion device 100. According to oneembodiment, the spring arm posts 404 and 408 push against a bottom sideof the dome 176.

As the plunger 144 reaches the end of its travel stroke, the force ofthe pressurization spring 140 on the plunger 144 overcomes the bias ofthe first and second spring arms 384 and 388, inducing the signalingpost 392 to extend outside the infusion device 100 and thereby signalthat delivery of the medicament is substantially complete.

FIGS. 19A and 19B respectively illustrate still another end-of-doseindicator (EDI) 424 and the operation thereof. As shown in FIG. 19A, theEDI 424 includes a post 428 having a helical face 432. The EDI 424 alsoincludes an arm 436 extending from an end of the post 428, and avertical extrusion or signaling post 440 extending from an end of thearm 436 through an EDI opening 444 (see FIG. 20A) in the top enclosure116 to be visible from outside the infusion device 100. According to oneembodiment, the EDI opening 444 is an arcuate slot. The post 428 alsohas base 448 for rotatably connecting the EDI 424 to the bottomenclosure 104.

FIG. 19B illustrates the helical face 432 contacting a side edge of theplunger 144. FIG. 20A illustrates the infusion device 100 in apre-activated state. According to one embodiment, the helical face 432of the EDI 424 bears against the edge of the plunger 144 throughout themotion of the plunger. Thus, as the plunger 144 travels upwardly withinthe cylindrical housing 200 subsequent to activation, the contactbetween the edge of the plunger 144 and the helical face 432 causes theEDI 424 to rotate. According to one embodiment, the interaction betweenthe helical face 432 and the edge of the plunger 144 during motion ofthe plunger 144 induces less than a full rotation of the post 428. Inother words, the pitch of the helical face 432 induces less than a fullrotation of the post 428 during the motion of the plunger 144.

As the EDI 424 rotates, the signaling post 440 correspondingly rotateswithin the EDI opening 444. And as the signaling post 440 reaches theend of the EDI opening 444, as shown in FIG. 20B, the EDI 424 indicatesthat delivery of the medicament is substantially complete.

Similar to FIGS. 19A and 19B, FIGS. 21A and 21B illustrate still anotherend-of-dose indicator (EDI) 452 and the operation thereof. As shown inFIG. 21A, the EDI 452 includes a post 456 having a helical face 460. Inaddition, the post 428 has a base 462 for rotatably connecting the EDI452 to the bottom enclosure 104. The EDI 452 also includes a signalingindicator 464 on a top thereof, the signaling indicator 464 beingvisible from outside the infusion device 100 through an EDI opening 468(see FIG. 22A) in the top enclosure 116.

FIG. 21B illustrates the helical face 460 contacting a side edge of theplunger 144. FIG. 22A illustrates the infusion device 100 in apre-activated state. According to one embodiment, the helical face 432of the EDI 424 bears against the edge of the plunger 144 throughout themotion of the plunger. Accordingly, as the plunger 144 travels upwardlywithin the cylindrical housing 200 subsequent to activation, the contactbetween the edge of the plunger 144 and the helical face 460 causes theEDI 424 to rotate. In comparison to the EDI 424 of FIG. 19A, the helicalface 460 has a finer pitch. Thus, the EDI 452 rotates more during thestroke of the plunger 144 and the EDI 424. According to one embodiment,the interaction between the helical face 460 and the edge of the plunger144 during motion of the plunger 144 induces at least one full rotationof the post 456. In other words, the pitch of the helical face 460induces at least one full rotation of the post 456 during the motion ofthe plunger 144. According to one embodiment, the EDI 452 rotates morethan one full rotation during the stroke of the plunger 144.

According to one embodiment, the signaling indicator 464 is, forexample, an arrow. Correspondingly, on exterior portion of the topenclosure 116 adjacent to the EDI opening 468, there is at least onemarker 472. As the EDI 452 rotates within the EDI opening 468 due to thestroke of the plunger 144, the rotation of the signaling indicator 464with respect to the marker 472 is visible from outside the infusiondevice 100 thereby indicating a progress of the delivery of themedicament.

According to one embodiment, the pitch of the helical face 460 isdefined to induce just less than two full rotations of the post 456during the stroke of the plunger 144. Accordingly, as shown in FIG. 22B,after traveling just less than 2 full rotations, the EDI 452 indicatesthat delivery of the medicament is substantially complete.

As shown in FIGS. 23A-23C, various markers may be employed adjacent anEDI opening on the top enclosure 116 to indicate progress of delivery ofthe medicament. For example, FIG. 23A illustrates a marker 476 thatincludes a scale with gradations. Such a marker 476 paired with anarcuate EDI opening can be employed with EDI 424. It will be generallyunderstood however, that various markers may also be employed withvariously-shaped EDI openings and various EDI embodiments.

FIG. 23B illustrates a marker 480 that includes icons denoting the stateof fullness of the reservoir 160. For example, one icon indicates thatthe reservoir 160 is substantially full, a middle icon indicates thatthe reservoir 160 is substantially half-full, and therefore thatdelivery of the medicament is substantially half complete, and a thirdicon indicates that the reservoir 160 is substantially empty, andtherefore that delivery of the medicament is substantially complete.

FIG. 23C illustrates a marker 484 that includes fraction icons denotingthe state of fullness of the reservoir 160 or the fraction of medicamentdelivery that is complete, depending upon the direction of rotation ofthe corresponding EDI. For example, if a clockwise-rotating EDI with anarrow signaling indicator were employed with the marker 484, the motionof such an EDI would indicate the state of fullness of the reservoir160. In contrast, if a counterclockwise-rotating EDI with an arrowsignaling indicator were employed with the marker 484, the motion ofsuch an EDI would indicate the fraction of medicament delivery that hasbeen completed.

FIGS. 24A and 24B illustrate a further end-of-dose indicator (EDI) 488and the operation thereof. According to one embodiment, the EDI 488 is apressure-sensitive strip 488. When the plunger 144 reaches the end ofits travel stroke, pressure of the plunger 144 (due to the force of thepressurization spring 140) is imparted to the pressure-sensitive strip488. The pressure against the pressure-sensitive strip 488 induces acolor change, thereby indicating that delivery of the medicament issubstantially complete. The color change is visible because the top ofthe reservoir (for example, a window therein) is transparent.

According to one embodiment, the EDI 488 is disposed within thereservoir 160, for example, on an interior surface of the transparentdome 176. At the end of the travel stroke of the plunger 144, thepressure of the plunger 144 against the reservoir dome seal 164 istransferred by the reservoir dome seal 164 to the pressure-sensitivestrip 488, inducing the color change thereof.

FIGS. 24A and 25A illustrate the infusion device 100 in a pre-activatedstate. According to one embodiment shown in FIGS. 24A and 25A, the EDI488 is disposed within the body of the infusion device 100 to be visiblefrom outside the infusion device 100. Additionally, the EDI 488 isdisposed such that as the plunger 144 reaches the end of its travelstroke, the foot 212 of the plunger 144 contacts the pressure-sensitivestrip 488 due to the force of the pressurization spring 140, and thepressure of the foot 212 against the pressure-sensitive strip 488induces the color change of the pressure sensitive strip 488. FIGS. 24Band 25B illustrate the infusion device 100 subsequent to foot 212contacting the pressure-sensitive strip 488 and inducing the colorchange, thereby indicating completion of the delivery of the medicament.

FIGS. 26A and 26B illustrate another end-of-dose indicator (EDI) 492 andthe operation thereof. According to one embodiment, the EDI 492 is a dyepack having at least two separated chambers 496 and 500. When theplunger 144 reaches the end of its travel stroke, pressure of theplunger 144 (due to the force of the pressurization spring 140) isimparted to the dye pack 492, rupturing a divider 504 between the twochambers 496 and 500. Once the divider 504 is ruptured, the contents ofthe two chambers 496 and 500 mix and the mixture changes color, therebyindicating that delivery of the medicament is substantially complete.

According to one embodiment, chamber 496 has a yellow dye and chamber500 has a blue dye. Once the divider 504 ruptures, the blue and yellowdyes mix and form a green dye, indicating that delivery of themedicament is substantially complete.

According to one embodiment, the EDI 492 is disposed within thereservoir 160, for example, on an interior surface of the transparentdome 176. At the end of the travel stroke of the plunger 144, thepressure of the plunger 144 against the reservoir dome seal 164 istransferred by the reservoir dome seal 164 to the dye pack 492, inducingthe color change thereof.

FIGS. 26A and 27A illustrate the infusion device 100 in a pre-activatedstate. According to one embodiment shown in FIGS. 26A and 27A, the EDI492 is disposed within the body of the infusion device 100 to be visiblefrom outside the infusion device 100. Additionally, the EDI 492 isdisposed such that as the plunger 144 reaches the end of its travelstroke, the foot 212 of the plunger 144 contacts the dye pack 492 due tothe force of the pressurization spring 140, and the pressure of the foot212 against the dye pack 492 ruptures the divider 504 and induces thecolor change of dye pack. FIGS. 26B and 27B illustrate the infusiondevice 100 subsequent to foot 212 contacting the dye pack 492 andinducing the color change, thereby indicating completion of the deliveryof the medicament.

FIG. 28 illustrates an embodiment of an infusion device 700 with aninjection port 704. The injection port provides access to an evacuatedor partially-filled reservoir 708, so that the patient can inject asubstance or combination of substances into the reservoir prior toactivation. Alternatively, a pharmaceutical manufacturer or pharmacistcould employ the injection port 704 to fill the infusion device 700 witha substance or combination of substances prior to sale. In substantiallyall other respects, the infusion device 700 is similar to thepreviously-described infusion device 100.

Operation of the infusion device 100 will now be described. Theembodiments of the present invention described above preferably includea push-button (activator button 128) design wherein the infusion device100 can be positioned and affixed to a skin surface, and energizedand/or activated by pressing the activator button 128. Morespecifically, in a first step, the patient removes the device from asterile packaging (not shown), removes a cover (not shown) of theadhesive pad 264. The patient also removes the needle cover 112. Uponremoval of the infusion device 100 from the package and prior to use(see, for example, FIGS. 1, 2, 4, and 5), the infusion device 100 in thepre-activated state allows the patient to inspect both the device andthe contents therein, including inspection for missing or damagedcomponents, expiration dates(s), hazy or color-shifted drugs, and soforth.

The next step is the positioning and application of the infusion device100 to the patient's skin surface. Like a medicinal patch, the patientfirmly presses the infusion device 100 onto the skin. One side of theadhesive pad 264 adheres to a bottom surface of the bottom enclosure 104and a bottom surface of the safety mechanism 108, and the opposing sideof the adhesive pad 264 secures the infusion device 100 to the skin ofthe patient. These bottom surfaces (of the bottom enclosure 104 and thesafety mechanism 108) can be flat, contoured, or shaped in any suitablefashion and the adhesive pad 264 is secured thereon. According to oneembodiment, prior to shipping, the cover of the adhesive pad 264, suchas a film, is applied to the patient-side of the adhesive pad 264 topreserve the adhesive during shipping. As noted above, prior to use, thepatient peels back the adhesive cover, thereby exposing the adhesive pad264 for placement against the skin.

After removing the adhesive cover, the patient is able to place theinfusion device 100 against the skin and press to ensure properadhesion. As noted above, once properly positioned, the device isactivated by depressing the activator button 128. This activation stepreleases plunger 144 and the pressurization spring 140, allowing aplunger 144 to press against the flexible film (reservoir dome seal 164)of the reservoir 160, thereby pressurizing the reservoir. Thisactivation step also serves to release the drive spring 148 from thedrive spring holder 260 of the rotor 136, thereby driving themicroneedles 152 to extend outside the infusion device 100 (through theopening 300 in the bottom enclosure 104 and the needle opening 156 ofthe safety mechanism 108) and seat the microneedles 152 within thepatient. Further, the activation step opens the valve 168, establishinga fluid communication path between the reservoir 160 and themicroneedles 152, via the channel 172 (see, for example, FIGS. 8-10). Asignificant benefit derives from the ability to achieve each of theseactions in a single push-button operation. Additionally, anothersignificant benefit includes the use of a continuous fluid communicationpath comprised entirely within the reservoir subassembly 120.

Once activated, the patient typically leaves the infusion device 100 inposition, or wears the device, for some period of time (such as tenminutes to seventy-two hours) for complete delivery of the reservoircontents. Substantial completion of delivery of the medicament isindicated by the EDI, for example, EDI 124. The patient then removes anddiscards the device with no damage to the underlying skin or tissue.Upon intentional or accidental removal, one or more safety featuresdeploy to shield the exposed microneedles 152. More specifically, whenthe infusion device 100 is removed by the patient from the skin, theadhesive pad 264 acts to deploy the safety mechanism 108 from theinfusion device 100, thereby shielding the microneedles 152, whichotherwise would be exposed upon removal of the infusion device 100 fromthe patient. When the safety mechanism 108 is fully extended, the safetymechanism 108 locks into place and prevents accidental injury orexposure to the microneedles 152. The safety features, however, can beconfigured to not deploy if the activator button 128 has not beendepressed and the microneedles 152 have not been extended, therebypreventing pre-use safety mechanism deployment. After use, the patientcan once again inspect the device to ensure the entire dose wasdelivered. For example, the patient can view the reservoir interiorthrough the transparent dome 176 and/or inspect the EDI 124.

The described embodiments are suitable for use in administering varioussubstances, including medications and pharmaceutical agents, to apatient, and particularly to a human patient. As used herein, apharmaceutical agent includes a substance having biological activitythat can be delivered through the body membranes and surfaces, andparticularly the skin. Examples, listed in greater detail below, includeantibiotics, antiviral agents, analgesics, anesthetics, anorexics,antiarthritics, antidepressants, antihistamines, anti-inflammatoryagents, antineoplastic agents, vaccines, including DNA vaccines, and thelike. Other substances that can be delivered intradermally orsubcutaneously to a patient include human growth hormone, insulin,proteins, peptides and fragments thereof. The proteins and peptides canbe naturally occurring, synthesized or recombinantly produced.Additionally, the device can be used in cell therapy, as duringintradermal infusion of dendritic cells. Still other substances whichcan be delivered in accordance with the method of the present inventioncan be selected from the group consisting of drugs, vaccines and thelike used in the prevention, diagnosis, alleviation, treatment, or cureof disease, with the drugs including Alpha-1 anti-trypsin,Anti-Angiogenesis agents, Antisense, butorphanol, Calcitonin andanalogs, Ceredase, COX-II inhibitors, dermatological agents,dihydroergotamine, Dopamine agonists and antagonists, Enkephalins andother opioid peptides, Epidermal growth factors, Erythropoietin andanalogs, Follicle stimulating hormone, G-CSF, Glucagon, GM-CSF,granisetron, Growth hormone and analogs (including growth hormonereleasing hormone), Growth hormone antagonists, Hirudin and Hirudinanalogs such as hirulog, IgE suppressors, Insulin, insulinotropin andanalogs, Insulin-like growth factors, Interferons, Interleukins,Leutenizing hormone, Leutenizing hormone releasing hormone and analogs,Low molecular weight heparin, M-CSF, metoclopramide, Midazolam,Monoclonal antibodies, Narcotic analgesics, nicotine, Non-steroidanti-inflammatory agents, Oligosaccharides, ondansetron, Parathyroidhormone and analogs, Parathyroid hormone antagonists, Prostaglandinantagonists, Prostaglandins, Recombinant soluble receptors, scopolamine,Serotonin agonists and antagonists, Sildenafil, Terbutaline,Thrombolytics, Tissue plasminogen activators, TNF-, and TNF-antagonist,the vaccines, with or without carriers/adjuvants, includingprophylactics and therapeutic antigens (including but not limited tosubunit protein, peptide and polysaccharide, polysaccharide conjugates,toxoids, genetic based vaccines, live attenuated, reassortant,inactivated, whole cells, viral and bacterial vectors) in connectionwith, addiction, arthritis, cholera, cocaine addiction, diphtheria,tetanus, HIB, Lyme disease, meningococcus, measles, mumps, rubella,varicella, yellow fever, Respiratory syncytial virus, tick bornejapanese encephalitis, pneumococcus, streptococcus, typhoid, influenza,hepatitis, including hepatitis A, B, C and E, otitis media, rabies,polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV,chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including BCG, gonorrhoea, asthma,atherosclerosis malaria, E-coli, Alzheimers, H. Pylori, salmonella,diabetes, cancer, herpes simplex, human papilloma and the like othersubstances including all of the major therapeutics such as agents forthe common cold, Anti-addiction, anti-allergy, anti-emetics,anti-obesity, antiosteoporeteic, anti-infectives, analgesics,anesthetics, anorexics, antiarthritics, antiasthmatic agents,anticonvulsants, anti-depressants, antidiabetic agents, antihistamines,anti-inflammatory agents, antimigraine preparations, antimotion sicknesspreparations, antinauseants, antineoplastics, antiparkinsonism drugs,antipruritics, antipsychotics, antipyretics, anticholinergics,benzodiazepine antagonists, vasodilators, including general, coronary,peripheral and cerebral, bone stimulating agents, central nervous systemstimulants, hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetrics, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,sedatives, sexual hypofunction and tranquilizers and major diagnosticssuch as tuberculin and other hypersensitivity agents as described inU.S. Pat. No. 6,569,143, entitled “Method of Intradermally InjectingSubstances”, the entire content of which is expressly incorporatedherein by reference.

Vaccine formulations which can be delivered in accordance with thesystem and method of the present invention can be selected from thegroup consisting of an antigen or antigenic composition capable ofeliciting an immune response against a human pathogen, which antigen orantigenic composition is derived from HIV-1, (such as tat, nef, gp120 orgp160), human herpes viruses (HSV), such as gD or derivatives thereof orImmediate Early protein such as ICP27 from HSVI or HSV2, cytomegalovirus(CMV (esp Human) (such as gB or derivatives thereof), Rotavirus(including live-attenuated viruses), Epstein Barr virus (such as gp350or derivatives thereof), Varicella Zoster Virus (VZV, such as gpl, IIand IE63) or from a hepatitis virus such as hepatitis B virus (forexample Hepatitis B Surface antigen or a derivative thereof), hepatitisA virus (HAV), hepatitis C virus and hepatitis E virus, or from otherviral pathogens, such as paramyxoviruses: Respiratory Syncytial virus(RSV, such as F and G proteins or derivatives thereof), parainfluenzavirus, measles virus, mumps virus, human papilloma viruses (HPV forexample HPV6, 11, 16, 18), flaviviruses (e.g. Yellow Fever Virus, DengueVirus, Tick-borne encephalitis virus, Japanese Encephalitis Virus) orInfluenza virus (whole live or inactivated virus, split influenza virus,grown in eggs or MDCK cells, or whole flu virosomes or purified orrecombinant proteins thereof, such as HA, NP, NA, or M proteins, orcombinations thereof), or derived from bacterial pathogens such asNeisseria spp, including N. gonorrhea and N. meningitidis (for examplecapsular polysaccharides and conjugates thereof, transferrin-bindingproteins, lactoferrin binding proteins, PilC, adhesins); S. pyogenes(for example M proteins or fragments thereof, C5A protease, lipoteichoicacids), S. agalactiae, S. mutans; H. ducreyi; Moraxella spp, including Mcatarrhalis, also known as Branhamella catarrhalis (for example high andlow molecular weight adhesins and invasins); Bordetella spp, includingB. pertussis (for example pertactin, pertussis toxin or derivativesthereof, filamenteous hemagglutinin, adenylate cyclase, fimbriae), B.parapertussis and B. bronchiseptica; Mycobacterium spp., including M.tuberculosis (for example ESAT6, Antigen 85A, -B or -C), M. bovis, M.leprae, M. avium, M. paratuberculosis M. smegmatis; Legionella spp,including L. pneumophila; Escherichia spp, including enterotoxic E. coli(for example colonization factors, heat-labile toxin or derivativesthereof, heat-stable toxin or derivatives thereof), enterohemorragic E.coli, enteropathogenic E. coli (for example shiga toxin-like toxin orderivatives thereof); Vibrio spp, including V. cholera (for examplecholera toxin or derivatives thereof); Shigella spp, including S.sonnei, S. dysenteriae, S. flexnerii; Yersinia spp, including Y.enterocolitica (for example a Yop protein), Y. pestis, Y.pseudotuberculosis; Campylobacter spp, including C. jejuni (for exampletoxins, adhesins and invasins) and C. coli; Salmonella spp, including S.typhi, S. paratyphi, S. choleraesuis, S. enteritidis; Listeria spp.,including L. monocytogenes; Helicobacter spp, including H. pylori (forexample urease, catalase, vacuolating toxin); Pseudomonas spp, includingP. aeruginosa; Staphylococcus spp., including S. aureus, S. Epidermidis;Enterococcus spp., including E. faecalis, E. faecium; Clostridium spp.,including C. tetani (for example tetanus toxin and derivative thereof),C. botulinum (for example Botulinum toxin and derivative thereof), C.difficile (for example clostridium toxins A or B and derivativesthereof); Bacillus spp., including B. anthracis (for example botulinumtoxin and derivatives thereof); Corynebacterium spp., including C.diphtheriae (for example diphtheria toxin and derivatives thereof);Borrelia spp., including B. Burgdorferi (for example OspA, OspC, DbpA,DbpB), B. garinii (for example OspA, OspC, DbpA, DbpB), B. afzelii (forexample OspA, OspC, DbpA, DbpB), B. andersonii (for example OspA, OspC,DbpA, DbpB), B. Hermsii; Ehrlichia spp., including E. equi and the agentof the Human Granulocytic Ehrlichiosis; Rickettsia spp, including R.rickettsii; Chlamydia spp., including C. Trachomatis (for example MOMP,heparin-binding proteins), C. pneumoniae (for example MOMP,heparin-binding proteins), C. psittaci; Leptospira spp., including L.interrogans; Treponema spp., including T. pallidum (for example the rareouter membrane proteins), T. denticola, T. hyodysenteriae; or derivedfrom parasites such as Plasmodium spp., including P. Falciparum;Toxoplasma spp., including T. gondii (for example SAG2, SAG3, Tg34);Entamoeba spp., including E. histolytica; Babesia spp., including B.microti; Trypanosoma spp., including T. cruzi; Giardia spp., includingG. lamblia; Leshmania spp., including L. major; Pneumocystis spp.,including P. Carinii; Trichomonas spp., including T. vaginalis;Schisostoma spp., including S. mansoni, or derived from yeast such asCandida spp., including C. albicans; Cryptococcus spp., including C.neoformans, as described in PCT Patent Publication No. WO 02/083214,entitled “Vaccine Delivery System”, the entire content of which isexpressly incorporated herein by reference.

These also include other preferred specific antigens for M.tuberculosis, for example Tb Ra12, Tb H9, Tb Ra35, Tb38-1, Erd 14, DPV,MTI, MSL, mTTC2 and hTCC1. Proteins for M. tuberculosis also includefusion proteins and variants thereof where at least two, preferablythree polypeptides of M. tuberculosis are fused into a larger protein.Preferred fusions include Ra12-TbH9-Ra35, Erd14-DPV-MTI, DPV-MTI-MSL,Erd14-DPV-MTI-MSL-mTCC2, Erd14-DPV-MTI-MSL, DPV-MTI-MSL-mTCC2,TbH9-DPV-MTI. Most preferred antigens for Chlamydia include for examplethe High Molecular Weight Protein (HWMP), ORF3, and putative membraneproteins (Pmps). Preferred bacterial vaccines comprise antigens derivedfrom Streptococcus spp, including S. pneumoniae (for example capsularpolysaccharides and conjugates thereof, PsaA, PspA, streptolysin,choline-binding proteins) and the protein antigen Pneumolysin (BiochemBiophys Acta, 1989, 67, 1007; Rubins et al., Microbial Pathogenesis, 25,337-342), and mutant detoxified derivatives thereof. Other preferredbacterial vaccines comprise antigens derived from Haemophilus spp.,including H. influenzae type B (“Hib”, for example PRP and conjugatesthereof), non typeable H. influenzae, for example OMP26, high molecularweight adhesins, P5, P6, protein D and lipoprotein D, and fimbrin andfimbrin derived peptides or multiple copy variants or fusion proteinsthereof. Derivatives of Hepatitis B Surface antigen are well known inthe art and include, inter alia, PreS1, PreS2 S antigens. In onepreferred aspect the vaccine formulation of the invention comprises theHIV-1 antigen, gp120, especially when expressed in CHO cells. In afurther embodiment, the vaccine formulation of the invention comprisesgD2t as hereinabove defined.

In addition to the delivery of substances listed above, the infusiondevice 100 can also be used for withdrawing a substance from a patient,or monitoring a level of a substance in the patient. Examples ofsubstances that can be monitored or withdrawn include blood,interstitial fluid or plasma. The withdrawn substances can then beanalyzed for analytes, glucose, drugs, and the like.

Although only a few exemplary embodiments of the present invention havebeen described in detail above, those skilled in the art will readilyappreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of the appended claims andequivalents thereof.

1. A drug delivery device, comprising: a body having a reservoirdisposed therein for containing a medicament; an injection needle forpenetrating the skin of a patient, the needle being in fluidcommunication with the reservoir; a pressurization unit and a plungermovable within the body under a force of the pressurization unit forcontacting the reservoir; and indicator means visible outside the devicefor indicating that delivery of the medicament is substantiallycomplete, wherein motion of the plunger activates the indicator means,and wherein the indicator means converts the motion of the plunger intomotion of the indicator means visible from outside the device.
 2. Thedevice according to claim 1, wherein the indicator means comprises: apost rotatably disposed within the body and having a helical face; anarm extending from an end of the post; and a vertical extrusionextending from an end of the arm through the body to be visible fromoutside the device; wherein the helical face of the post bears againstan edge of the plunger such that the motion of the plunger rotates thepost from an initial position to a second position, indicating thatdelivery of the medicament is substantially complete.
 3. The deviceaccording to claim 1, wherein the indicator means comprises: a mainbody; and a signaling post connected with the main body; wherein as theplunger reaches an end of its travel stroke, the plunger contacts theindicator means due to a force of the pressurization unit, and apressure of the plunger against the end-of-dose indicator induces thesignaling post to extend outside the device.
 4. The device according toclaim 3, wherein a base of the signaling post comprises a differentcolor than the remainder of the signaling post, thereby signaling thatdelivery of the medicament is substantially complete when the color ofthe base of the signaling post is visible outside the device.
 5. Thedevice according to claim 4, wherein the indicator means furthercomprises: first and second arms extending from a first end of the mainbody; and a spring arm extending from the first end of the main body;wherein the signaling post extends from an end of the second arm.
 6. Thedevice according to claim 4, wherein the indicator means furthercomprises: at least one stabilizing arm extending from the body forstabilizing the indicator means during movement thereof; and a first armextending from the main body; wherein the signaling post extends from anend of the first arm.
 7. The device according to claim 1, wherein theindicator means comprises: a pressure-sensitive strip; wherein when theplunger reaches an end of its travel stroke, the plunger contacts thepressure sensitive strip due to the force of the pressurization unit anda pressure of the plunger against the pressure-sensitive strip induces acolor change of the pressure-sensitive strip for indicating thatdelivery of the medicament is substantially complete.
 8. The deviceaccording to claim 1, wherein the indicator means comprises: a dye pack;wherein when the plunger reaches an end of its travel stroke, theplunger contacts the dye pack due to the force of the pressurizationunit and a pressure of the plunger against the dye pack induces a colorchange of the dye pack for indicating that delivery of the medicament issubstantially complete.
 9. The device according to claim 1, wherein thepressurization unit comprises a pressurization spring.
 10. The deviceaccording to claim 7, wherein: the end-of-dose indicator is disposedwithin the reservoir; and at the end of the plunger's travel stroke, thepressure of the plunger against the reservoir induces the color changeof the pressure-sensitive strip.
 11. The device according to claim 7,wherein: the reservoir comprises a transparent dome and a flexible,non-distensible reservoir dome seal; the pressure-sensitive strip isdisposed on an interior surface of the dome; and at the end of theplunger's travel stroke, the reservoir dome seal transfers the pressureof the plunger to the pressure-sensitive strip, inducing the colorchange thereof.
 12. The device according to claim 8, wherein: theend-of-dose indicator is disposed within the reservoir; and at the endof the plunger's travel stroke, the pressure of the plunger against thereservoir induces the color change of the dye pack.
 13. The deviceaccording to claim 12, wherein: the reservoir comprises a transparentdome and a flexible, non-distensible reservoir dome seal; the dye packis disposed on an interior surface of the dome; and at the end of theplunger's travel stroke, the reservoir dome seal transfers the pressureof the plunger to the dye pack, inducing the color change thereof. 14.The device according to claim 1, wherein the end-of-dose indicatorconverts the motion of the plunger into motion of the end-of-doseindicator visible from outside the device.
 15. The device according toclaim 14, wherein throughout the motion of the plunger, the end-of-doseindicator bears against an edge of the plunger.
 16. The device accordingto claim 15, wherein the end-of-dose indicator comprises: a postrotatably disposed within the main body and having a helical face; anarm extending from an end of the post; and a vertical extrusionextending from an end of the arm through the body to be visible fromoutside the device; wherein the helical face of the post bears againstthe edge of the plunger such that the motion of the plunger rotates thepost from an initial position to a second position, indicating thatdelivery of the medicament is substantially complete.
 17. The deviceaccording to claim 16, wherein the interaction between the helical faceand the edge of the plunger during the motion of the plunger inducesless than a full rotation of the post.
 18. The device according to claim16, wherein a pitch of the helical face induces less than a fullrotation of the post during the motion of the plunger.
 19. The deviceaccording to claim 16, wherein the interaction between helical face andthe edge of the plunger during the motion of the plunger induces atleast one full rotation of the post.
 20. The device according to claim16, wherein a pitch of the helical face induces at least one fullrotation of the post during the motion of the plunger.
 21. The deviceaccording to claim 16, wherein the body includes: an arcuate openingthrough which the vertical extrusion extends; and a marker disposedadjacent to the opening, indicating a progress of the delivery of themedicament.
 22. The device according to claim 14, wherein theend-of-dose indicator comprises: a main body; and a signaling postconnected with the main body; wherein as the plunger reaches an end ofits travel stroke, the plunger contacts the end-of-dose indicator due toa force of the pressurization spring, and a pressure of the plungeragainst the end-of-dose indicator induces the signaling post to extendoutside the device.
 23. The device according to claim 22, wherein theend-of-dose indicator further comprises: first and second arms extendingfrom a first end of the main body; and a spring arm extending from thefirst end of the main body; wherein the signaling post extends from anend of the second arm.
 24. The device according to claim 23, wherein:the plunger comprises a plunger tab extending from an edge thereof; andthe plunger tab contacts the first arm to convert the motion of theplunger into motion of the signaling post.
 25. The device according toclaim 24, wherein: the reservoir comprises a dome and a flexible,non-distensible reservoir dome seal; the spring arm contacts the dome tobias the end-of-dose indicator toward a pre-activated position; and asthe plunger reaches the end of its travel stroke, the force of thepressurization spring overcomes the bias of the spring arm inducing thesignaling post to extend outside the device.
 26. The device according toclaim 22, wherein a base of the signaling post comprises a differentcolor than the remainder of the signaling post, thereby signaling thatdelivery of the medicament is substantially complete when the color ofthe base of the signaling post is visible outside the device.
 27. Thedevice according to claim 23, wherein: the body includes a cylindricalhousing in which the plunger moves; and the cylindrical housing includesa channel movably housing the main body of the end-of-dose indicator.28. The device according to claim 22, wherein the end-of-dose indicatorfurther comprises at least one stabilizing arm extending from the mainbody for stabilizing the end-of-dose indicator during movement thereof;and a first arm extending from the main body; wherein the signaling postextends from an end of the first arm.
 29. The device according to claim28, wherein: the plunger comprises a plunger tab extending from an edgethereof; and the plunger tab contacts the main body to convert themotion of the plunger into motion of the signaling post
 30. The deviceaccording to claim 29, wherein: the end-of-dose indicator furthercomprises at least one spring arm with a spring arm post extending froman end thereof; during motion of the signaling post, the spring arm postcontacts the dome to bias the end-of-dose indicator toward apre-activated position; and as the plunger reaches the end of its travelstroke, the force of the pressurization spring overcomes the bias of thespring arm inducing the signaling post to extend outside the device. 31.The device according to claim 28, wherein: the body includes acylindrical housing in which the plunger moves; the cylindrical housingincludes a channel movably housing the main body of the end-of-doseindicator; and the at least one stabilizing arm contacts an exterior ofthe cylindrical housing for stabilizing the end-of-dose indicator duringmovement thereof.